The invention relates compositions comprising the synergistic combination of platelet activating factor (PAF) antagonists with leukotriene D.sub.4 (LTD.sub.4) antagonists and the use thereof to treat allergic reactions.
The mechanism of pathogenesis associated with allergic reactions involves an antigen-induced release of a variety of allergic mediators from mast cells, basophils, and possibly macrophages. These mediators include histamine, leukotrienes and PAF all of which posses a broad spectrum of potent biological activities. [Schleimer, R. P., Am. Rev. Respir. Dis., 133, 614-617 (1986)]. [Barnes, P. J., J. Allergy Clin. Immunol., 81,152-160 (1988)]. Assessment of the precise contribution of each individual allergic mediator to the pathology of allergic reactions is unknown.
For example, allergic asthma involves the antigen-induced release of allergic mediators from mast cell which subsequently cause bronchoconstriction, mucus secretion, and changes in capillary permeability which, in combination with the production of chemotactic agents, leads to the influx into the lung of inflammatory cells. The mediators rapidly induce a narrowing and occluding of the bronchial lumen of the airways and, over time, the development of a chronic inflammatory condition in the lungs. Inflammation of the airways may be essential to the establishment of bronchial hyperresponsiveness which is the characteristic abnormality of asthma. [Chung, K. F., Thorax, 41, 657-662 (1986)]. It has been difficult to identify the predominant mediator(s) of allergic asthma, but in recent years a number of lines of evidence strengthen the concept that the bronchoactive peptidoleukotrienes (LTC.sub.4, LTD.sub.4, and LTE.sub.4) and PAF may be important in this disease process. LTD.sub.4 and PAF have been identified in body fluids during an episode of asthma. They are both potent mediators of inflammation, and can reproduce some of the pathophysiological features of the disease when administered to animals and man. [O'Donnell, M. in Therapeutic Approaches to Inflammatory Diseases, A. J. Lewis, N. S. Doherty and N. R. Ackerman, eds., Elsevier Science Publishing Co., New York, 169-193 (1989)].
Compounds which prevent the effects of the mediators are thus of interest in treating allergic reactions. However, since allergic reactions are complex processes that are probably not attributable to a single causative factor, a potent, specific, agent by itself may not be particularly effective in preventing allergic reactions.